Submissions for variant NM_002880.4(RAF1):c.845G>A (p.Arg282Gln)

gnomAD frequency: 0.00001  dbSNP: rs752713997

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000598002	SCV000709735	uncertain significance	not specified	2018-03-06	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: gnomAd 3:12641904 C / T- in 3/111662 Europeans and 1/30782 South Asian, not in ClinVar, HGMD, or Google search; fairly well conserved; predicted to be benign by polyphen
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216616	SCV001388421	uncertain significance	RASopathy	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 282 of the RAF1 protein (p.Arg282Gln). This variant is present in population databases (rs752713997, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 503548). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAF1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001547003	SCV001766619	likely benign	not provided	2020-09-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002448840	SCV002676672	uncertain significance	Cardiovascular phenotype	2024-07-28	criteria provided, single submitter	clinical testing	The p.R282Q variant (also known as c.845G>A), located in coding exon 7 of the RAF1 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000598002	SCV003929308	uncertain significance	not specified	2023-04-17	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.845G>A (p.Arg282Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251422 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.845G>A has been reported in the literature in an individual with Hypertrophic Cardiomyopathy without evidence for causality (Ceyhan-Birsoy_2018). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=3) and Likely Benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001547003	SCV005409142	uncertain significance	not provided	2024-03-19	criteria provided, single submitter	clinical testing	PP2